Risk Factors and Definition of Younger-Onset Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Cirrhosis.

BACKGROUND & AIMS: Cirrhosis from metabolic dysfunction-associated steatotic liver disease (MASLD) usually develops with advancing age, yet a subset of patients presents at younger ages. We examined genetic and metabolic factors associated with younger-onset MASLD cirrhosis. APPROACH AND RESULTS: Adults with biopsy-proven MASLD enrolled in the NASH CRN were included. DNA was genotyped, and a genetic risk score (GRS) was calculated as the sum of risk alleles in PNPLA3 and TM6SF2 plus the wild-type HSD17B13 allele, dichotomized at the median (low vs high), in addition to evaluation of previously published weighted GRSs. Younger-onset cirrhosis was defined as the youngest quartile among participants with cirrhosis. Multivariable logistic regression evaluated factors associated with younger-onset cirrhosis. Among 2,395 participants, 234 (9.8%) had MASLD cirrhosis (median age 58.4 years, body mass index (BMI) 34.9 kg/m2, 66% with type 2 diabetes mellitus [T2DM]). Younger-onset cirrhosis was defined as the lowest quartile, which was <50 years and was associated with a lower prevalence of the protective HSD17B13 variant (24% vs 34%, p=0.004). Compared with non-cirrhotic MASLD participants under 50 years (n=999), those with cirrhosis more often had T2DM, BMI ≥35kg/m2, higher alkaline phosphatase, and lower ALT. In multivariable models adjusting for demographic and metabolic factors, high GRS (OR 2.33, 95%CI: 1.26-4.23; p=0.006) and T2DM (OR 3.74, 95%CI: 2.08-6.82; p<0.001) remained independently associated with cirrhosis under age 50. CONCLUSIONS: One-quarter of participants with MASLD cirrhosis present before age 50 years and have distinct features, including higher genetic risk and a greater prevalence of T2DM.